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First published online May 14, 2009, 10.2967/jnumed.108.060103
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Journal of Nuclear Medicine Vol. 50 No. 6 920-926
© 2009 by Society of Nuclear Medicine
doi: 10.2967/jnumed.108.060103

Basic Science Investigation

Inflammatory Cytokines and Hypoxia Contribute to 18F-FDG Uptake by Cells Involved in Pannus Formation in Rheumatoid Arthritis

Tamiko Matsui1, Norihito Nakata1, Shigenori Nagai2,3, Akira Nakatani1, Miwako Takahashi4, Toshimitsu Momose4, Kuni Ohtomo4 and Shigeo Koyasu2

1 Research Center, Nihon Medi-physics Co., Ltd., Chiba, Japan; 2 Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan; 3 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan; and 4 Department of Radiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Correspondence: For correspondence or reprints contact either of the following: Akira Nakatani, Research Center, Nihon Medi-physics Co., Ltd., Kitasode 3-1, Sodegaura, Chiba 299-0266, Japan. E-mail: akira_nakatani{at}nmp.co.jp

Assessment of the activity of rheumatoid arthritis (RA) is important for the prediction of future articular destruction. 18F-FDG PET is known to represent the metabolic activity of inflammatory disease, which correlates with the pannus volume measured by MRI or ultrasonography. To evaluate the correlation between 18F-FDG accumulation and RA pathology, we assessed 18F-FDG accumulation in vivo using collagen-induced arthritis (CIA) animal models and 3H-FDG uptake in vitro using various cells involved in arthritis. Methods: 18F-FDG PET images of rats with CIA were acquired on days 10, 14, and 17 after arthritis induction. The specimens were subsequently subjected to macroautoradiography, and the 18F-FDG accumulation was compared with the histologic findings. 3H-FDG uptake in vitro in inflammatory cells (neutrophils, macrophages, T cells, and fibroblasts) was measured to evaluate the contributions of these cells to 18F-FDG accumulation. In addition, the influence on 3H-FDG uptake of inflammatory factors, such as cytokines (tumor necrosis factor {alpha} [TNF{alpha}], interleukin 1 [IL-1], and IL-6), and hypoxia was examined. Results: 18F-FDG PET depicted swollen joints, and 18F-FDG accumulation increased with the progression of arthritis. Histologically, a higher level of 18F-FDG accumulation correlated with the pannus rather than the infiltration of inflammatory cells around the joints. In the in vitro 3H-FDG uptake assay, fibroblasts showed the highest 3H-FDG uptake, followed by neutrophils. Although only a small amount of 3H-FDG was incorporated by resting macrophages, a dramatic increase in 3H-FDG uptake in both fibroblasts and macrophages was observed when these cells were exposed to inflammatory cytokines, such as TNF{alpha} and IL-1, and hypoxia. Although neutrophils showed relatively high 3H-FDG uptake without activation, no increase in 3H-FDG uptake was observed in response to inflammatory cytokines. 3H-FDG uptake by T cells was much lower than that by other cells. Thus, fibroblasts and activated macrophages contribute to a high level of 18F-FDG accumulation in the pannus, and hypoxia as well as cytokine stimulation significantly increases 18F-FDG uptake by these cells. Conclusion: 18F-FDG accumulation in RA reflects proliferating pannus and inflammatory activity enhanced by inflammatory cytokines and hypoxia. 18F-FDG PET should be effective for quantifying the inflammatory activity of RA.

Key Words: 18F-FDG • rheumatoid arthritis • fibroblast • cytokine • hypoxia

Shigeo Koyasu, Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8585, Japan. koyasu{at}sc.itc.keio.ac.jp

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.


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